The majority of patients having formed kidney stones composed of calcium oxalate and/or apatite demonstrate hypercalciuria when compared to normal subjects without a personal or family history of stones. Stone formers exhibit hypercalciuria at all levels of dietary Ca intake as well as increased urinary and salivary Ca when fasting suggesting a cellular Ca leak. The resulting elevations of urinary Ca concentrations appear to be an important determinant of Ca-salt crystalluria and stone growth. In addition, Ca-stone formers demonstrate hypophosphatemia, augmented fractional renal PO4 excretion, and elevations of fasting salivary PO4 concentrations. On the average, serum immunoreactive parathyroid hormone concentrations are normal among Ca-stone formers but in recent observations we have shown that plasma 1,25-(OH)2-vitamin D concentrations are elevated in comparison to normal subjects. These high plasma 1,25-(OH)2-D levels are inversely related to serum PO4 concentrations. Furthermore, dietary PO4-deprivation in healthy women, but not men, results in a fall in serum PO4 and a reciprocal rise in plasma 1,25-(OH)2-D concentrations. Since PO4 deprivation in animals, regardless of parathyroid function, activates renal 1,25-(OH)2-D synthesis, these observations suggest that a primary abnormality in PO4 homeostasis leading to activation of the renal 25-OH-D-1alpha-hydoxylase may be a fundamental abnormality underlying Ca-stone disease. We propose to continue studies designed to clarify the apparent disordered regulation of PO4 and vitamin D metabolism in Ca-stone formers (males:females equals 3:1) and the differences in the responses of women and men to PO4-deprivation. We wish to evaluate factors affecting serum PO4 measurements, study the turnover and metabolism of 3H-1,25-(OH)2-D3, evaluate plasma 1,25-(OH)2-D with respect to diurnal variation, age, sex, estrogens, dietary Ca, PO4 and Mg, and thiazide dijuretics, search for differences of in vitro RBC PO4 transport between normals and Ca-stone formers, establish the basis for the low bone density in stone formers and re-evaluate the classification of Ca-stone disease.